Bombesin is a 14-amino acid peptide originally isolated from the skin of the European frog Bombina bombina (Anastasi A., et a., Experientia, 1971;27:166). It belongs to a class of peptides which share structural homology in their C-terminal decapeptide region (Dutta A. S. Small Peptides; Chemistry, Biology, and Clinical Studies, Chapter 2, pp 66-82). At present, two mammalian bombesin-like peptides have been identified (Battey J., et a., TINS, 1991;14:524), the decapeptide neuromedin B (NMB) and a 23-residue amino acid, gastrin-releasing peptide (GRP). Bombesin-like immunoreactivity detected in mammalian brain (Braun M., et al., Life. Sci., 1978;23:2721) and GI tract (Walsh J. H., et al., Fed. Proc. Fed. Am. Soc. Exp. Biol., 1979;38:2315) together with the more recent studies measuring mRNA levels in rat brain (Battey J., et al., TINS, 1991;14:524), point to the widespread distribution of both NMB and GRP in mammalian peripheral and central nervous systems.
NMB and GRP are believed to mediate a variety of biological actions via actin upon the corresponding bombesin receptors including their action as autocrine growth factors in human small cell lung carcinoma and other cancers (Taylor J. E., et al., Ann. N.Y. Acad. Sci., 1988;547:350; Rozengurt E., Ibid., 277; Cuttitta F., et al., Nature, 1985;316:823; Kozacko M. F., et al., Proc. Natl. Acad. Sci. USA, 1996;93:2953), secretion of other neuropeptides and hormones (Ghatei M. A., et al., J. Clin. Endocrinol. Metab., 1982;54:98), contraction of smooth muscle (Erspamer V., et al., Pure Appl. Chem., 1973;35:463), behavioral effects (Kulkosky P. J. et al., Physiol. Behav. 1982;28:505; Gmerek D. E., et al., Peptides, 1983;4:907; Cowan A., Ann. N.Y. Acad. Sci., 1988;547:204), thermoregulation (Brown M. R., et al., Ann. N.Y. Acad. Sci., 1988;547:174), effects on satiety (Kirkham T. C., et al., Pharma. Biochem, Behav., 1995;52:101 and Ladenheim E. E., et al., Eur. J. Pharmacol., 1994;271:R7), regulation of circadian rhythms (Albers H., et al., J. Neurosci., 1991;11:846), regulation of gastric acid section (Walsh J. H., Ann. Rev. Physiol., 1988;50:41) and gastrointestinal motility (see Lebacq-Verheyden A., et al., in Handbook of Experimental Pharmacology, 1990;95 (Part II) and references therein), effects on locomotor activity and nociception (Pert A., et al., Brain Res., 1980;193:209), effects on memory (Flood J. F., et al., Brain Res., 1988;460:314), and interaction with 5HT-containing neurones (Pinnock R. D., et al., Brain Res., 1994;653:199 and Pinnock R. D., et al., J. Physio., 1991;440:55).
Accordingly, compounds capable of antagonizing the effects of NMB and/or GRP at bombesin receptors will be useful in treating or preventing a variety of disorders including depression, psychoses, seasonal affective disorders, cancer, feeding disorders, gastrointestinal disorders including colitis, Crohn's disease and inflammatory bowel disease, sleeping disorders, and memory impairment.